This invention relates to novel compositions of matter containing optically pure (-)-zileuton. These compositions possess potent activity in treating asthma, ulcerative colitis, rheumatoid arthritis, psoriasis, allergic rhinitis and other diseases including those that would benefit from a selective inhibition of 5-lipoxygenase. By virtue of the antioxidant activity of (-)-zileuton, the compositions are also useful for treating atherosclerosis. Optically pure (-)-zileuton provides this treatment while substantially reducing adverse effects including, but not limited to, headache, nausea, fatigue, diarrhea, dyspepsia, chills, dizziness and paresthesia, which are associated with the administration of the racemic mixture of zileuton. Also disclosed are methods for treating the above described conditions in a human while substantially reducing the adverse effects that are associated with the racemic mixture of zileuton by administering the (-) isomer of zileuton to said human.
The active compound of these compositions and methods is an optical isomer of zileuton. The preparation of racemic zileuton is described in U.S. Pat. No. 4,873,259 and European application 279263. The medicinal chemistry of zileuton is described in Bell et al. [Intl. J. Imm. Pharmacol. 14, 505-510 (1992)], Abraham et al. [Europ. J. Pharmacol. 217, 119-126 (1992)], Carter et al. [J. Pharm. Exp. Ther. 256, 929-937 (1991)], and Sirois et al. [Agents and Actions 34, 117-120 (1991)]. Chemically, the active compound is the (-) isomer of N-(1-benzo[b]thien-2-ylethyl)-N-hydroxyurea, hereinafter referred to as zileuton. It appears to have the S absolute stereochemistry as shown in formula I: ##STR1##
(-)-Zileuton, which is the subject of the present invention, is not presently commercially available. All of the medicinal chemistry that has been reported has utilized the racemic mixture, which is available for research purposes only.
Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. There is no correlation between nomenclature for the absolute stereochemistry and for the rotation of an enantiomer. Thus, D-lactic acid is the same as (-) lactic acid, and L-lactic acid is (+). For a given chemical structure, these chiral compounds exist as a pair of enantiomers which are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture.
Stereochemical purity is of importance in the field of pharmaceuticals, where 12 of the 20 most prescribed drugs exhibit chirality. A case in point is provided by the L-form of the beta-adrenergic blocking agent, propranolol, which is known to be 100 times more potent than the D-enantiomer.
Furthermore, optical purity is important since certain isomers may actually be deleterious rather than simply inert. For example, it has been suggested that the D-enantiomer of thalidomide was a safe and effective sedative when prescribed for the control of morning sickness during pregnancy, while the corresponding L-enantiomer has been believed to be a potent teratogen.
Notwithstanding the paper by Sweeny and Nellans (below), neither the separation of racemic zileuton nor the synthesis of (-) zileuton has been described. However, the enantioselective synthesis of the (+)-isomer from L-(+)-lactic acid has been described by Hsiao and Kolasa [Tetra. Letters 33, 2629-2632 (1992)]. The selective glucuronidation of S-(-)-zileuton and the enhancement of that reaction by the R-isomer in dog liver microsomes has been reported by Sweeney and Nellans [J. Biol. Chem. 267, 13171-13174 (1992)]. No medicinal chemistry of the individual enantiomers is reported.
Racemic zileuton has been in clinical trials in the United States for use in rheumatoid arthritis [Weinblatt et al., J. Rheumatology 19, 1537-1541 (1992)], for asthma [Israel et al., N. Eng. J. Med. 323, 1740-1744 (1990)], for ulcerative colitis [Laursen et al., Lancet 335, 683-6835 (1990)] and for allergen induced nasal congestion [Knapp, N. Eng. J. Med. 323, 1745-1748 (1990)]. The results of the preliminary clinical studies indicate that racemic zileuton may be clinically useful in all of these disease states because of its suppression of leukotriene production.
The leukotrienes are a family of highly potent biological substances derived from arachidonic acid and are believed to be involved in mediating a spectrum of human disorders. Considerable evidence suggests that the leukotrienes contribute to the asthmatic response and that they are mediators of other inflammatory diseases (see Carter, et al. op. cit.). Because several 5-lipoxygenase metabolites are likely to be generated at sites undergoing pathological reactions, and because these metabolites then act in concert to produce the clinical condition, it is thought advantageous to inhibit the formation of the constellation of metabolites to achieve therapeutic benefit. Since 5-lipoxygenase is the first enzymatic step in the conversion of arachidonic acid to leukotrienes, its inhibition should decrease the production of all of the pro-inflammatory metabolites. Racemic zileuton has been found to be a very selective inhibitor of mammalian 5-lipoxygenase with little inhibitory effect on human platelet 12-lipoxygenase, soybean 15-lipoxygenase or sheep seminal vesicle cyclooxygenase. In human volunteers doses of 800 mg p.o. twice per day for four weeks resulted in 75 to 85% decreases in LTB.sub.4 and statistically significant improvement in symptoms of rheumatoid arthritis. (Weinblatt op. cit.) One hundred percent of the patients receiving racemic zileuton reported an adverse event during the four week trial. The adverse events included headaches, nausea, fatigue, diarrhea, dyspepsia, chills, dizziness, paresthesia and infections.
In pre-clinical trials, racemic zileuton was absorbed rapidly in all of the species tested with T.sub.max values ranging from 15 minutes to one hour. The elimination half life for the racemic compound, estimated from oral studies, varied markedly among species from 20 minutes in monkeys to 7 hours in dogs. While clinical trials have so far been limited to rheumatoid arthritis, asthma, ulcerative colitis and allergen induced nasal congestion, it is believed that as a result of its 5-lipoxygenase inhibitory activity racemic zileuton may also be useful to treat gout, psoriasis, adult respiratory distress syndrome, Crohn's disease, endotoxin shock, inflammatory bowel disease and ischemia induced by myocardial or cerebral injury.
Thus it would be particularly desirable to find a compound with the advantages of the racemic mixture of zileuton which would not have the aforementioned disadvantages.